Opioid and melanocortin receptors: do they have overlapping pharmacophores?

Abstract

We have identified compound 1 as a novel ligand for opioid and melanocortin (MC) receptors, which is derived from the overlapping of a well known structure for the delta opioid receptor, 2,6-dimethyltyrosine (Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), and a small molecule for the MC receptor, Tic-DPhe(p-Cl)-piperidin-4-yl-N-phenyl-propionamide. Ligand 1 showed that there is an overlapping pharmacophore between opioid and MC receptors through the Tic residue. The ligand displayed high biological activities at the delta opioid receptor (Ki = 0.38 nM in binding assay, EC(50) = 0.48 nM in GTP-gamma-S binding assay, IC(50) = 74 nM in MVD) as an agonist instead of an antagonist and showed selective binding affinity (IC(50) = 2.3 muM) at the MC-3 receptor rather than at the MC-5 receptor. A study of the structure-activity relationships demonstrated that the residues in positions 2, 3, and the C-terminus act as a pharmacophore for the MC receptors, and the residues in positions 1 and 2 act as a pharmacophore for the opioid receptors. Thus, this structural construct can be used to prepare chimeric structures with adjacent or overlapping pharmacophores for opioid and MC receptors.

• Authors: Yeon Sun Lee, Richard S Agnes, James P Cain, Vinod Kulkarni, Minying Cai, Christine Salibay, Kathy Ciano, Ravil Petrov, Alexander Mayorov, Josef Vagner, Dev Trivedi, Peg Davis, Shou-wu Ma, Josephine Lai, Frank Porreca, Ruben Vardanyan, Victor J Hruby
• Journal: Biopolymers (Biopolymers) Vol. 90 Issue 3 Pg. 433-8 ( 2008) ISSN: 0006-3525 [Print] United States
• PMID: 17657709 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: (c) 2007 Wiley Periodicals, Inc.

Chemical References

• Ligands
• Receptor, Melanocortin, Type 3
• Receptors, Opioid, delta
• Cyclic AMP

Topics

• Binding, Competitive
• Cell Line
• Cyclic AMP (analysis)
• Humans
• Inhibitory Concentration 50
• Kidney (cytology)
• Ligands
• Radioligand Assay
• Receptor, Melanocortin, Type 3 (agonists, metabolism)
• Receptors, Opioid, delta (agonists, metabolism)
• Structure-Activity Relationship